9 alpha-halo-11beta-acyloxy steroids and processes for their manufacture



United States Patent 2,986,574 9a-HALOPIIB-ACYLOXY STEROIDS AND r1200 ESSES FOR TITHEIKMANUFACTURE Cecil H. Robinson, Clifton, and Lawrence E. Finckenor, Lyndhurst, N.J., assignors-v to Schering Corporation, Bloomfield, N.J., a corporation of New Jersey No Drawing. 'Filed Mar. 13, 1959, Ser. No. 799,096 26 Claims. (Cl. 260397.45)'

This invention relates to novelsteroid compounds and to processes for their manufacture;

More particularly, this invention relates to a novelmethod for converting a M -steroid to a 9a-halogeno- 1 lfi-acyloxy analog.

The valueof 9,3,11,8-oxido steroids iswell known in the art. By reacting samewith ahydrogen halide there is produced a 9a-halo-l'lfl-hy'droxy system which is of great importance in the field of'therapeutics. Among the many uses are conversion to potent therapeutic agents. such as 9a-fiuorohydrocortisone, 9a-fluoropreda nisolone, dexamethasone andthe like. In the androstane series the 9B,11,B0Xld0 group is similarly transformable to provide for compounds such as 9cc-fl11010-11 fl-hydroxy- 17-methyltestosterone and. a host of other therapeutically active substances.

Heretofore, 9,11-oxido steroids of the pregnane and androstane series have been prepared by treating the M -analog withhyprobromous acid -(or its chemical equivalent) thus forming a bromohydrin. The bromohydrin upon treatment with a base undergoes. elimination of the elements of hydrogen bromide and thus forms an epoxide ring. In general, the yields .on such transformations are in' the range of5065% of theoretical. In our process the yields on converting a.A -bond to a 9a-halogeno llfl-acylate are in the range of 90-95%. In many instances, these'compounds are transformable to 9,8,11B-epoxides also in 90% yield. A. further advantage of this invention, is. that the 9a-halo-11fi-acylates are generally easily isolated by aqueous precipitation and filtration. The halohydrins obtained by the known. procedures are generally oily or resinous in nature necessitating isolation by extraction withsolvents.

Our novel process provides for the transformation of a M -steroid of the pregnane or androstane series to a 9u-halogen0-1lB-acyloxy' analog. The halogeno group is preferably bromo, although chloro and iodo may also be employed. The structure of the acyloxy group is not critical. Representative of acyloxy groups envisioned as falling within'our invention are alkanoyloxy, e.g.,. those derived from hydrocarbon carboxylic acids such as formic, acetic, propionic, diethylacetic, caproic, capric and the like. Other carboxylic' acid esters such as benzoate are alsoapplicable; Similarly, substituted: alkanoyloxy groups are utilizable such as tn'fluoroacetoxy, dichloroacetox-y. Other acyl groups such. as derived from a sulfonic acid are also applicable, e.g., p-toluenesulfonyloxy, mesyloxy, benzenesulfonyloxysandthe like. Ounpreferred substituent is formoxy or trifluoroacetoxy, since these groups have been found to be more easily removed under alkaline conditions than most others, thus generatingthe 95,11fi-oxido group.

The reagent which acts upon the M -bond is composed of a source of halonium ion such as an N ha1ogeno amide or imide together with the appropriate acid. For example, the reagent comprised of N-bromosuccinimide and trifluoroacetic acid acts upon a M -bond toform a 9a.-.bromo-1 113-triliuoroacetoxy group. We

7 2,986,574 Patented May 30, 1961 2: have found that the presence-ofadditional common acylate ion is helpful in obtaining higher yields. Thus, in theforegoing example, it is advantageous'to add a salt oftrifiuoroacetic acidtothe reaction mixture. The salt is preferably one formed with an alkali metalsuch as sodium, potassium or lithium, or an alkalineearthmetal such as calcium, or a pseudo metal such as ammonium. The reaction is preferably carried out in the presence of an inertorganic solvent such as tetrahydrofuran, carbon tetrachloride, chloroform, and the like. The choice of solvent is not critical, since the solvent-merely acts as a diluent forthe reactants. We have found-that the yields when applied in the pregnane series are generally in excess of of theory,

Our novel 9a-halogeno-llfi-esters under basic conditions suchas sodium methoxide inmethanol; potassium,

4,9 (,1 l)-pregnadiene-17a,21-diol-3,20:dione, 2l-acetate,.

1,4,9(1'1)-pregnadiene-17u,2l-diol-3,201dione 21 -ace tate,

16-methyl a or ,6) -l ,4,9( 1 1 )-pregnatriene- :,21-di01-3,

ZO-dione 2l-alkanoate,

4,9( 1 l -androstadienel7a-methyl-l7-fl-ol-3-one,

1, 4,-9(11)Fandrostatriene-3,17-dione and the like- Likewise, our processimay be applied to a preparation starting with, for example, pregnane, or a.llopr egnane)- 1le-ol-3-,20-dione.- Dehydration of the llw-h'ydroxy group via the l'l-p-tosylateforms the M -bond which isthen subjected to our reagent -andiprocess. The presence of an. ester group on the llfl-hydroxyl" permits ef-' fectingreactions-on other partsof'the molecule such as; bromination and dehydrobromination of the A-ring: or; halogenation and acetoxylation at C-21 without participationby the reactive 11/3-hydroxy group.

Furthermore, in the case of the pregnane'series, the presence of the. Ila-ester grouppermits. oxidativecleavageof theside chain so as to forma 17-keto substituted androstane analog. Thus, 90,fl-bIOIIlO-1lflr-ElCfllOXYPICdDlS- olone upon reactionwith sodium bismuthateor chromic' acid yields 9u-bromo-1lfi-acetoxy-l,4-androstadiene-3,17- dione. Treatment of this latter diene with strong alkali efiects formation .of 9,8,llfl-oxidm1,'4-androstadiene+3,'17- dione. The oxido compoundis. convertible to the..va1u-,. able substance 9a-fluoro-1,4-androstadiene-1lfi-ol-3,17- dione according to the procedure described in copending applicationofQNob'ile; Serial No; 776;4 01', filed November 26, 1958, now=U-.S; Patent No. 2,955,118.

Inaddition .to. their; use. as intermediates in the. preparation of 9fi,11;3-epoxides, our.--9uhalogeno-1'1,8-esters are therapeutically valuable as anti-inflammatory. agents.

The vllfi-ester markedly reduces the untowardsalt. retainingefiect of thehalogen, especially chloro and thus. finds: utility in. topical application. such as: in unguents. or creams..

The following examples are illustrative of'our process, its application and of the novel intermediates produced thereby,

3 EXAMPLE 1 9a-bromo-1 ,4-pregnadiene-11;8,1 7u,21-tri0l-3,20- dione-I 1 B-formate 21 acetate To a stirred solution of 1.0 g. of 1,4,9(11)-pregnatriene-i17a,2l-diol-3,20-dione 21-acetate in 40 ml. of formic acid containing 4.0 g. of sodium formate is added 395 mg. N-bromoacet-amide. Stirring is continued for 3 hours, and the reaction mixture is then poured into 400 ml. of water, filtered and the residue washed with water and dried. The dried residue weighs 1.26 g. and consists of 9a-bromo-l,4-pregnadiene-l1B,17u,21-triol-3,20- dione-llfi-formate 21-acetate. Purification is effected by crystallization from acetone-hexane, M.P. 210213 C. dec.,

A2532 239 m (e 13,800)

Analysis.-Ca1cd. for C I-I O Br: C, 56.58; H, 5.74, Br, 15.69: Found: C, 56.27; H, 5.68; Br, 14.12.

EXAMPLE 2 '9a-brom0-1,4-pregnadiene-11,8,1 7a,21-tri0l-3,20- dione-I Ifl-trifluoroacetate 21 -acetate Analysis.-'-Calcd. for C H O BrF C, 52.00; H, 4.89; Br, 13.84. Found: C, 52.20; H, 4.89; Br, 13.76.

EXAMPLE 3 Qa-ChlOrO-l ,4-p regnadiene-1 1B, 17u,Z1-tri0l-3,20-

' dione-I] fi-formate 21 -acetate To a stirred solution of 1.0 g. 1,4,9(11)-pregnatriene- 17a,2l-diol-3,20-dione 21-acetate in 40 ml. formic acid containing 4.0 g. sodium formate is added 382 mg. N- chlorosuccinimide followed immediately by 2.7 ml. of 1 N-hydrochloric acid. Stirring is continued for 3 hours at room temperature, and the reaction mixture is then poured into water (400 ml.). Filtration, followed by Water-washing and drying of the residue gives 1.14 g. of 9a-chloro-1,4 pregnadiene l1,3,l7a,21-triol-3,20-di0nellfi-formate Zl-acetate. This compound, after crystallization from acetone-hexane, has M.P. 25 8-262 C. dec.,

Analysis.Calcd. for C H O Cl: C, 61.99; H, 6.28; Cl, 7.64. Found: C, 61.64; H, 6.58; CI, 7.36.

EXAMPLE 4 9a-br0m0-4-pregnene41 8.1 7a-21-tri0l-3,20-dione- 11 p-formate 21 acetate To'a stirred solution of 1.0 g. of 4,9(11)-pregnadiene- 17a,2l-diol-3,20-dione 21-acetate in 40 ml. of formic acid containing 4 g. potassium formate is added 395mg. N-bromoacetamide. Stirring is continued for 3 hours, the reaction mixture was poured into 400 ml. water and filtered. The residue is Washed and dried yielding 1.24 g; of

lljS-fbrmate ZI-acetate 9a-brpmo-4-pregnene-1lp,17a,2l-triol-3,20-dione 4 EXAMPLE 5 9u-br0mo-4-pregnene-1 1 3,17u-21-tri0l-3,20-di0ne- 1 1 B-trifluoracetate 21 -acetate The llfi-trifluoracetate of this example is prepared from 4,9(11) pregnadiene 17a,21 diol 3,20 dione 2l-acetate exactly as described for Example 2. The yield of 9a bromo 4 pregnene 11,B,17e,21 triol- 3,20-dione-lIB-trifluoracetate ZJI-acetate, which exhibited my 240 me (6 13,800) is 92% EXAMPLE 6 9a bromo 4 pregnene 11,8 ol 3,20 dione 11/3- trifluoracetate To a stirred solution of 1.0 g. of 4,9(11)-pregnadiene- 3,20-dione in 25 ml. of tetrahydrofuran and 25 ml. of trifluoracetic acid is added N-bromoacetamide (450 mg), the temperature being maintained at about 25 C. by cooling. Stirring at room temperature is continued for 3 hours, and the reaction mixture is poured into 500 ml. water and filtered. The residue is washed with water and dried, giving 1.47 g. 9a-bromo-4-pregnene-1 1,8-01- 3,20-dione-1lfl-trifluoroacetate, A max. 240 me. (2: 14,100).

EXAMPLE 7 Qfl-HB-oxido-I,4-pegnadiene-17m,21-di0l-3,20-di0ne (A) From the compound of Example 1, the 1118- formate (570 mg.) is suspended in methanol (35 ml.) and to this suspension is added, dropwise with stirring, 2.85 ml. of 1 N-aqueous sodium hydroxide solution. Stirring is continued for 16 hours at room temperature, and the reaction mixture is then poured into 400 ml. water. The mixture is extracted with methylene chloride which upon evaporation yields the crude 95,115- oxido-Zl-ol (350 mg). The substance is acetylated at 0-21 in pyridine and acetic anhydride for 1 /2 hours, the acetylated product being isolated by water precipitation and filtration. The water-washed and dried residue weighs 350 mg, is crystallized from acetone-hexane to yield pure 9,13,11B-oxido 21-acetate of this example identical with authentic material as evidenced by melting point, mixed melting point, comparison of infrared spectra and paper chromatography.

(B) The compound of Example 2 is dissolved in 100 ml. absolute ethanol containing 4 g. potassium acetate and the solution is refluxed for 17 hours. The reaction mixture is concentrated to about 20 ml., water is added, and the mixture is extracted with methylene chloride. The extracts are washed with water, dried with magnesium sulfate, filtered and evaporated in vacuo to yield the crude product (750 mg). This material, on paper chromatography using a propylene glycol toluene-dioxane system, shows spots corresponding to about 80% of the 913,116-oxido 21-acetate and about 20% of the corresponding 2l-alcohol. Reacetylation at 0-21, using pyridine-acetic anhydride at room temperature, gives 750 mg. of product, which after filtration through Florisil in methylene chloride-ether (1:9) gives pure the 9B,-1l[3- oxido 21-acetate of this example, identical with authentic material (melting point, mixed melting point and comparison of infrared spectra).

EXAMPLE 8 9,8,11,8-oxz'd0-4-pregnene-1 7a,21-diol-3,20-di0ne 21 -acetate From the compound of Example 5, a solution of 1. 0 g.

- 917. bromo 4 pregnene 11B,17uc,21 triol 3,20-

dione llfl-trifluoracetate 2l-acetate in 20 ml. absolute ethanol (70 ml.) containing potassium acetate (3 g.) is refluxed for l7hours. The reaction mixture is concentrated in vacuo and water is added, the mixture then being extracted with methylene chloride. The extracts are washed with water, dried over magnesium sulfate andievaporated in vacuo; to yield520 mgacrudeiproduct;

(75%). This material is reacetylated atCl-Zlairipyri: dine-acetate anhydridemt .roomtemperature, and the reactylated materialis crystallized from acetone-hexaneto yield pure 95,116 oxido 4 pregnene 176 21"- diol 3,20-dione 2l-acetate identicalwith an authentiesample as demonstrated by melting-point, mixed melting point and comparison ofinfrared spectra.

EXAMPLE9 9,3,1I13-oxido-4-pregnene-3,20dione The llB-trifluoracetate (from Example 6; 1.0. g.) is. suspended in methanol (80 ml.) and to this suspension is.

added, dropwise with stirring, N-aqueous sodium hydroxide solution (4.0 ml.) at room temperature. Stirring is continued for 16 hours-at room temperature, and the" reaction'mixture is poured into 'water- (1 liter). The steroid is isolated by filtration; and the water-washed and dried residue weighs 700 mg. and consists of 95,11,8- oxido-4-pregnene-3,20-dione. Crystallization from acetone-hexane gives material, the infrared spectrum (in. Nujol) of which matches the infrared spectrumof' an" authentic sample.

EXAMPLE 10 9u-brom0-1 ,4-androstadiene-1 1 3-01-3 ,1 7-di0ne-1Jfltrifluoro-acetate- The requisite intermediate, 1,4,9(11)-androstatriene- 3, l7-dione, is prepared as follows:

A solution of llfi-hydroxy 1,4 androstadiene3,l7- dione (935 mg.) in dimethylformamide (11 ml.) and pyridine (1 ml.) is cooled to 0 C., and methane sulphonyl chloride (0.784 g.) is added dropwise, with stirring. Stirring at room temperature is continued for 27 hours, and the reaction mixture is thendiluted with water, extracted with methylenechloride and the extracts washed with sodium bicarbonate solution and water. Evaporation of the dried (MgSO extracts in vacuo yieldedthe crude product (770 mg; 88%).

After filtration through Florisil in ether, 640 mg. of the desired product is obtained. Crystallization from acetone-hexane yields 480 mg. of analytically pure triene, M.P. 164-167",

AMeOH max To a stirred solution of the l,4,9(11)-andr0statriene (1.0 g.) in tetrahydrofuran (20 ml.) and trifluoracetic acid (20 ml.) is added N-bromoacetamide (530 mg), the temperature being kept at about 25 C. by cooling. Stirring is continued, at room temperature, for 3 hours, and the reaction mixture is then poured into water (400 ml.) and filtered. The residue. is. washed with water, and dried, to yield 9a-bromo-1,4-androstadiene- 11B ol-3,17 dione-11B trifluoracetate. 160 g,, showing;

EXAMPLE 11 Conversion of 9a-bromo 1,4-andr0stadiene-1Idol-3,1 7- dione-11,3 trifluoracctate t0 95,1][3 oxido 1,4-androstadiene-3,17-dione The llfi-trifluoracetate from Example 10 (1.0 g.) in methanol (60 ml.) is treated with N-aqueous sodium hydroxide solution (4.2 ml.) at room temperature, with stirring. The stirred solution is left" at room temperature for 8 hours, and the mixture is then poured into water (1 liter). The steroid is isolated by filtration, and the residue is washed With Water and dried to yield 572 mg. (91%) of 9;9,11;3-oxid0 1,4 androstadiene-3,17.-dione. Purification isetfected by crystallization from. acetonehexane, M.P. 164-165 T dione;(1'" g.) in' tetrahydrofuran (30 ml.) i and trifluoF acetic acid (30 ml) is added N-bromoaeetamide (530 mg;')',, the temperature being maintainedat about 25"" by cooling; Stirring; at, room temperature: iscontinued for 3 hours, and the reaction'mix'ture is poured into Water (500 ml.) andfiltered; The residue is washed with waterand dried; yielding. 9,a-.bromo-4-androstene- 1 1;9-ol-3,17-dione-l lflatrifluoracetate (1.57" g.)

EXAMPLE 13.

Conversion of 9a-.brom0-4.-androstene- 11fl-ol 3;17-dione- 1 LB-trifluoracetateto 9,6,1]firoxidor4-androstene-3fl 7- dione To the: 11 fl-trifluoracetate: from Example 121 (500 mg.) in methanoli (40 ml.) is. added aqueous N sodium=hy-' droxide. solution (2.1 11113). at'room; temperature with. stirring: The;stirredlmixture is-left art room.tempera"- ture for; 8 hours,.and' is then pouredintowater (5.00 ml.) and filtered." The residue is washed'withswaterzand. dried? to give; 560 mg; of.9B,l1fl-oxid0-4 androstane-3,17-dione. Purificatiomis effected'by crystal: lizationfrom acetone-hexane, M.P. 180, identicalwitlr: authentic materialas determinedby mixed melting point and comparison of infrared spectra.

EXAMPLE 14' 9a-i0do-1 ,4-pregnadiene-1l [3,1 7a,21-triol-3,-20-di0ne- 115,21 -diacetate To a stirred solution of 1,4,9(l'l) pregnatriene-l7a, 2l-diol-3,20-dione 21-acetate (5.0-g.) and'lithium acetate (20 g.) in glacial acetic acid. (200 ml.) is added. N-iodosuccinimide (3.3' g.). Stirring is continued, at. room temperature for 17 hours, and the reaction mixture is then poured into Water (1000 1111.). The resulting mixture --is filtered,. and the residue is washed with water and dried to give. a quantitative yield of crude product. Crystallization from ethyl acetate gives pure 9a-iodo-l,4 pregnadiene- 11fi,17,21 triol-3;20-dione- 11fi,21-diacetate, M.P. -l50 dec., [0] (dioxane),

Anaylsis.--Calcd. for C H O- I: C, 52:64; H, 5348';- I,'.. 22.25. Found: C, 52.52; H, 5.30; I,.23.88.

EXAMPLE 15 9u-br0m0-1,4-pregnadiene-J 1,9,1 7a,2l -tri0l-3,20di0ne.-.- 1113,21-diacetate To a stirred solution of 1,4,9"(l1) pregnatriene-176t,21-

75; (40.ml.) containing: litliium acetate (4 g) 'is -added A 236 m (e 15,600)

Analysis.-Calcd. for C H O Cl: C, 62.69; H, 6.52; Cl, 7.40. Found: C, 62.66; H, 6.60; Cl, 7.01.

M53? 241 m (e 14,300)

EXAMPLE 1s 9u-br0m0-16fl-methyl-1,4-pregnadiene-1Ifi,17a,21-triol- 3,20-dione-1 1 B-trifluoracetate 21 -acetate A solution of 16 3 methyl 1,4,9( 11) pregnatrienel7a,2l-dio1-3,20-dione Zl-acetate (1.0 g.) in tetrahydrofuran (40 ml.) and trifluoracetic acid 40 ml.) is treated with N-bromoacetamide (381 mg.) in the manner of the preceding example to give the compound of this example.

EXAMPLE 19 To a stirred solution of one gram of l7a-methyl- 4,9(1l)-androstadieue-l7 8-ol-3-0ne in glacial acetic acid (40 ml.) containing lithium acetate (4 g.) is added N-bromoacetamide (471 mg.) and the mixture is stirred at room temperature for 17 hours. The reaction mixture is then poured into water (400 ml.), filtered, and the residue is washed with water and dried to give the crude product. Crystallization from acetone-hexane gives 9abromo-l7o -methyl-4-androstene-115,17,6-diol-3 one 11/3 acetate.

EXAMPLE 20 Conversion of 9a-br0m0-17a-methyl 4 androstened] B,

1 7fi-di0l-3 -0ne-1 1 fl-acetate to 96,11,8-oxid0-1 7a-methyl- 4-andr0stene-17fi-ol-3-0ne To the compound of the preceding example (500 mg.) in methanol (20 ml.) is added aqueous 2 N-sodium hydroxide solution (2.6 m1.) and the resulting solution is refluxed for 17 hours. The reaction mixture is then cooled, neutralized with acetic acid, poured into water and filteredQ The residue is washed with water and dried, to give 9,3,1lfi-oxido-17a-methyl-4-androstene-l718-01-3-one.

EXAMPLE 21 9a-br0m 0-1 ,4-pregnadiene-1 1 6,1 7a,21-tri0l-3,20-di0n e- 1 1 B-acetate One gram of 9a-bromo1,4-pregnadiene-115,111,21- triol-3,20-dione-l1,8,2l-diacetate (from Example 15) is suspended in'0.27 N methanolic perchloric acid (60 ml.) and the suspension is stirred at room temperature for 17 hours- Water (400ml) is added and the resulting mixtureis filtered. The residue is washed with water and dried to give crude product. "Crystallization from ace:

tone-hexane yields the compound of this example as a crystalline solid.

EXAMPLE 22 17,20; 20,21 -bismethylenedioxy derivative of Qa-bromo- 1,4-pregnadiene-11/3,17a,21-triol-3,20-di0ne-1Iii-acetate The compound of the preceding example (500 mg.) is dissolved in chloroform (20 ml.) and formaldehyde (5 ml.; 37%) and concentrated hydrochloric acid (5 ml.) are added. The resulting mixture is stirred vigorously at room temperature for 48 hours, and is then evaporated in vacuo to low volume. Water is then added, and the mixture is filtered. The residue is washed with water, dried and crystallized from acetone-hexane to give the compound of this example.

EXAMPLE 23 Conversion of the bismethylenedioxy derivative of 904- (A) The compound of the preceding example (1.0 g.) is dissolved in ethanol (40 ml.) and 2 N-aqueous sodium hydroxide solution (5 ml.) is added. The resulting solu tion is refluxed for 17 hours, and is then cooled and neutralized with acetic acid. Evaporation in vacuo to low volume and filtration gives crude product which consists substantially of the bisme'thylenedioxy derivative of 913,1lfi-oxido-1,4-pregnadiene-l7u,2l-diol-3,20-dione.

(B) The above crude product is dissolved in 60% aqueous formic acid (50 ml.) and the resulting solution is left at room temperature for three days. Water precipitation, filtration and drying of the residue gives a crude product which consists substantially of 9,B,llfl-oxido-l,4-pregnadiene-l7a,21-diol-3,20-dione.

We claim:

1. A member of the group consisting of 9a-hal0-l15- R-l7a,21-dihydroxy-3,ZO-diketo-M-pregnenes, the corresponding A -analogs and the 2l-lower fatty acid esters thereof wherein R is an acyloxy group having up to eight carbon atoms and the 9a-halo substituent has an atomic weight greater than 19.

2. A member of the group consisting of 9a-halo-A pregnene-llfi-R-l7u,2l-diol-3,20-diones wherein R is a member of the group consisting of lower alkanoyloxy and halogenated lower alkanoyloxy and the 2l-lower fatty acid esters thereof and the 9u-halo substituent has an atomic weight greater than 19.

3. A member of the group consisting of ll-lower alkanoyl and ll-halogenated lower alkanoyl-9a-halo-hydrocortisones and the 2l-lower alkanoyl esters thereof wherein the 9a-h'alo substituent has an atomic weight greater than 19.

4. A member of the group consisting of ll-lower alkanoyland ll-halogenated lower alkanoyl 9a -haloprednisolones and the 2l-lower alkanoyl esters thereof wherein the 9a-halo substituent has an atomic weight greater than 19.

5. A steroid of the group consisting of A -pregnenes of the general formula:

(EBAY C= 0 ber of the class consisting of H and lower alkyl and R is a member of the class consisting of lower alkanoyl and halogenated lower alkanoyl.

6. 9a bromo 1,4 pregnadiene 115,17a,21 triol- 3,20-dione-115-formate 21-acetate.

7. 9a bromo -1,4 pregnadiene 115,17a,21 triol- 3,20-dione-115-trifluoracetate 21-acetate.

8. 9a chloro 1,4 pregnadiene 11fi,17oc,21 triol- 3,20-dione-115-formate 2l-acetate.

' 9. 9a bromo 4 pregnene 115,17a,21 triol 3,20- dione-l l5-formate 21-acetate.

10. 9c: bromo 4 pregnene 115,17a,21 triol 3,20- dione-115-trifluoracetate 21-acetate.

11. 9a bromo 4 pregnene 115 ol 3,20 dione- 1 1 p-trifluoracetate.

12. 9oz iodo 1,4 pregnadiene l15,17a,21 triol- 3,20-dione-115,21-diacetate.

13. 9a bromo 1,4 pregnadiene 11 3,17a,21 triol- 3,20-dione-115,21-diacetate.

14. 9a chloro 1,4 pregnadiene 115,17u,21 triol- 3,20-dione-1 15,21-diacetate.

15. 9a bromo 16a methyl 1,4 pregnadiene 115, 17a,2l-trio1-3,20-dione-115-trifluoracetate 21-acetate.

16. 9a bromo 165 methyl 1,4 pregnadiene- 115,17a,2l triol 3,20 dione 115 trifluoracetate 21- acetate.

17. 9a bromo 1,4 pregnadiene 1l,8,17a,2l triol- 3,20-dione-1 l5-acetate.

18. 9a bromo 1,4 androstadiene 115 ol 3,17- dione-l l 5-trifluoracetate.

19. 9a bromo 17a 175-diol-3-one-1 15-acetate.

20. The process of preparing a steroid of the pregnane and androstane series having a 9a-halogen substituent and an ll-substituent of the group consisting of lower alkanoyloxy, halogenated lower alkanoyloxy, mesyloxy, and tosyloxy which comprises reacting the corresponding A -steroid of the series with an N-haloamide of a carboxylic acid, the halo substituent having an atomic weight greater than 19, in the presence of an acid selected from the group consisting of lower alkanoic acids, halogenated methyl 4 androstene 115,

lower alkanoic acids, methanesulfonic acid, and p-toluenesulfonic acid.

21. In the process for preparing a 9a-halogeno-115- ester of the pregnane series the step of converting a A -steroid of the series into the corresponding 9abromo-115-ester compound by reacting the former with an N-bromoamide of a carboxylic acid in the presence of a lower alkanoic acid.

22. The process of claim 21, wherein the reaction is carried out in the additional presence of a salt of the lower alkanoic acid.

23. The process of claim 21, wherein the alkanoic acid is formic.

24. The process of claim 21, wherein the alkanoic acid is trifluoracetic.

25. A member of the group consisting of 9a-halo-115- R-l-hydroXy-A -androstenes and the A -dehydro analogs thereof wherein R is a member of the group consisting of lower alkanoyloxy and halogenated lower alkanoyloxy and the 9a-halo substituent has an atomic weight greater than 19.

26. A compound of the group consisting of steroids of the 17-R-pregnane and 175-hydroxyl androstane series having a 9a-ha1o substituent, said substituent having an atomic weight greater than 19, and a -substituent selected from the group consisting of lower alkanoyloxy, halogenated lower alkanoyloxy, mesyloxy, and tosyloxy, wherein R is a member of the group consisting of hydrogen and a-hydroxyl.

References Cited in the file of this patent UNITED STATES PATENTS 2,800,489 Reichstein July 23, 1957 2,806,863 Herr Sept. 17, 1957 2,816,902 Gould et al. Dec. 17, 1957 2,837,464 Nobile June 3, 1958 2,852,511 Fried Sept. 16, 1958 2,852,538 Scheri et al Sept. 16, 1958 2,864,835 Gould et a1 Dec. 16, 1958 2,937,975 Figdor et a1. May 24, 1960 

1. A MEMBER OF THE GROUP CONSISTING OF 9A-HALO-11BR-17A,21-DIHYDROXY-3,20-DIKETO-$4-PREGNENES, THE CORRESPONDING $1-ANALOGS AND THE 21-LOWER FATTY ACID ESTERS THEREOF WHEREIN R IS AN ACYLOXY GROUP HAVING UP TO EIGHT CARBON ATOMS AND THE 9A-HALO SUBSTITUENT HAS AN ATOMIC WEIGHT GREATER THAN
 19. 